PROJECT SUMMARY Frontotemporal dementia (FTD) is associated with severe atrophy of the frontal and temporal lobes and debilitating behavioral deficits including social-indifferency, anxiety and compulsive-like behaviors. It is the second most common type of dementia after Alzheimer?s, and there is no cure. The pathogenic mechanisms at all levels, from cellular and synaptic to neural circuits are largely unknown. A hexanucleotide (G4C2) repeat expansion (HRE) in the C9ORF72 gene is the most common familial type of FTD and amyotrophic lateral sclerosis (ALS). We have adopted a unique AAV mouse model expressing 66-G4C2 HREs to study the neurotoxic effects of C9FTD on prefrontal neurophysiology. The AAV-(G4C2)66 mice fully recapitulate the neuropathological and clinical phenotypes, offering an excellent model for investigating the neurophysiological mechanisms underlying behavioral deficits of C9FTD. Neuroimaging studies have shown specific atrophy in the medial prefrontal cortex (mPFC) and downstream subcortical regions including the basolateral amygdala (BLA) and nucleus accumbens (NAc) in patients with FTD. Layer V (LV) pyramidal neurons in the mPFC exert top-down control of neural circuits active during behaviors that are preferentially disrupted by FTD. Emerging evidence suggests intrinsic neuronal excitability deficits as well as changes in synaptic AMPA receptor (AMPAR) composition in prefrontal circuits in FTD pathogenesis and behavioral symptoms. Using AAV-(G4C2)66 mice, I found that mutant mPFC LV pyramidal neurons become profoundly hypoexcitable at 11-months-old, suggesting that the mPFC becomes hypo-functional under FTD conditions. Importantly, increasing the neuronal excitability, even at such a late disease stage, rescued the marked social behavior deficits observed in these mutant mice. We hypothesize that hypofrontality can impair synaptic connections and efficacy within the mPFC as well as the mPFC-BLA and mPFC-NAc circuits thereby weakening top-down cognitive control of behaviors and contributing to FTD behavioral symptoms. We will employ electrophysiological, chemogenetic, optogenetic and behavioral approaches to test this hypothesis in the following specific aims. Specific Aim 1 will investigate the alterations of LV pyramidal membrane excitability in the mPFC of aged AAV-(G4C2)66 mice and investigate the role of hypofrontality in C9FTD-related behaviors in these mice. Specific Aim 2 will delineate synaptic and mPFC-BLA/mPFC-NAc circuitry deficits and their roles in behavioral dysfunction in aged AAV-(G4C2)66 mice. This proposal is highly innovative and significant because it uses a multidisciplinary strategy to test a novel hypothesis and advance our understanding of the cellular and circuit basis of FTD social dysfunction. Ultimately, such knowledge has the potential for developing novel therapeutic approaches to alleviate behavioral deficits in patients with FTD.